BCL6 promotes CCR2-driven CNS infiltration of encephalitogenic Th17 cells.

BCL6, a transcription factor central to T follicular helper (TFH) cell differentiation, has recently been identified as a key regulator of T cell-mediated neuroinflammation. While previous research has established a connection between Th17 cells and B cell responses in autoimmune diseases, most notably in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis-the role of BCL6 in T cell subsets beyond TFH cells remains unclear. In this study, we explored the impact of T cell-specific BCL6 deficiency on EAE progression. Our findings reveal that mice with BCL6-deficient T cells display significantly reduced disease severity in a B cell-independent model, characterized by decreased infiltration of pathogenic T cells, B cells, and myeloid cells into the central nervous system (CNS). Interestingly, BCL6 deficiency resulted in an increased number of inflammatory Th17 cells in peripheral organs including the spleen and lymph nodes, but a notable reduction of these cells in the CNS. We also discovered that BCL6-deficient Th17 cells exhibited impaired migration in response to the Th17-attracting chemokine CCL2. Moreover, the adoptive transfer of BCL6-deficient, MOG-specific Th17 cells failed to induce EAE, likely due to their diminished responsiveness to the CCR2-CCL2 chemotactic axis, which is crucial for CNS infiltration. These results suggest that BCL6 expression in T cells is critical for the migration of inflammatory Th17 cells into the CNS, contributing to neuro-autoimmunity. Our study identifies a novel role for BCL6 in regulating T cell migration during neuroinflammation and underscores its potential as a therapeutic target in multiple sclerosis.